The broad long-term goal of the research proposed in this application is to provide detailed information bearing on the pathways of responsiveness in vivo to allografted tissues and organs. The approach that is outlined in this application involves the study of responses of mice to allografts and xenografts and is based in part on the view that rigorous analysis of such responses in animals, whose immunologic reactivity has been impaired or otherwise altered by mutation, can be especially helpful in revealing the normal pathways of responsiveness. The specific aims of this study are as follows: 1. To determine the role and mechanisms of action of CD4+8- lymphocytes in the rejection of allografts that differ from their host with respect to Class I MHC antigens only; Class II MHC antigens only; or minor H antigens only; and in the rejection of Class I disparate allografts by mice that lack CD8+ cells because of their failure to produce beta-2 microglobulin. 2. To determine the origin and nature of the factors that are responsible for the genetically determine differences in the responses of mice of various inbred lines to grafts of rat tissues and organs.